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Biomarkers of Mineralocorticoid Receptor Activation

a mineralocorticoid receptor and biomarker technology, applied in the field of biomarkers of the mineralocorticoid receptor activation, can solve the problems of serious adverse side effects of mr antagonist administration in a patient, and the effect of mr activation in the cardiovascular system may occur,

Inactive Publication Date: 2011-10-20
INST NAT DE LA SANTE & DE LA RECHERCHE MEDICALE (INSERM) +2
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0081]The method of the invention may be useful for classifying patients affected by cardiovascular disease and then may be used to choose the accurate treatment for said patient. For example, patients classified as responder or non responder may thus receive an appropriate amount of the MR antagonist or aldosterone synthase inhibitor. Such a method may thus help the physician to make a choice on a therapeutic treatment. Costs of the treatments may therefore be adapted to risk of the patients.

Problems solved by technology

Deleterious effects of MR activation in the cardiovascular system may thus occur even in the absence of hyperaldosteronism (Funder J W, 2006) and plasma levels of aldosterone do not provide indication on the MR activation in the cardiovascular system.
Furthermore, administration of a MR antagonist in a patient may be accompanied with serious adverse side effects such as hyperkalemia.

Method used

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  • Biomarkers of Mineralocorticoid Receptor Activation
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Examples

Experimental program
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Effect test

example 1

[0116]MR and GR transgenic mice: Mineralocorticoid receptor (MR) and glucocorticoid receptor (GR) transgenic mice allowed conditional expression of the human MR or GR, respectively. MR and GR transgenic mice were obtained by breeding the in-house generated acceptor mice that allowed conditional, inducible expression of hMR or hGR when crossed with appropriate transactivator mice. These conditional transgenic models have been described in Ouvrard-Pascaud et al. (2005) and Sainte-Marie et al. (2007). To identify genes selectively modulated by MR in the heart, the MR and GR acceptor mice were crossed with the MHC-tTA transactivator mice provided by G. Fishman, Columbia University, NY, USA) (Yu et al. 1996) allowing cardiomyocyte-specific expression of hMR and hGR, respectively. This resulted in 4 fold overexpression of MR or 3 fold increase glucocorticoid binding in the heart of MR or GR conditional mice, respectively, as compared to control littermates. To avoid early embryonic lethal...

example 2

[0134]The plasma level of Lcn2 / NGAL has been measured in a population of healthy subjects.

[0135]Men and women aged between 18 and 85 years-old were included in the study, provided that they had presented no acute pathology in the past 7 days and were not under any cardiovascular treatment. Further exclusion criteria for healthy controls were: known high blood pressure (greater than 140 / 90 mmHg or greater than 160 mm Hg if older than 65); known renal failure, known diabetes, pregnancy, cancer diagnosed within the past 5 years or evolutive neoplasia, chronic liver pathology, connectivitis, Crohn's disease, evolutive tuberculosis, exertional angina, acute coronarien syndrome, history of coronopathy, carotidien endarterectomy and known abdominal aortic aneurysm.

[0136]The plasma level of Lcn2 / NGAL of the healthy subjects was generally comprised between 40 and 80 μg / ml.

[0137]The plasma level of Lcn2 / NGAL of patients affected with a cardiovascular disease, diabetes, obesity or metabolic sy...

example 3

[0138]Chronic overexpression of MR or GR in cardiomyocytes may lead to altered signaling pathways, representing adaptations of the cells, different from those induced by short-term corticosteroid treatment. To analyze the molecular consequences of chronic MR activation in vivo in the heart, we investigated cardiac gene expression of MR-cardiac mice using Cardiochips®, i.e. microarrays including 5419 genes that had been selected for their involvement in cardiovascular and / or skeletal muscle normal and pathological functioning. Cardiomyocyte MR overexpression for 6 weeks resulted in about 24 up-regulated and 23 down-regulated genes. Interestingly, most of them differed from GR-regulated genes that were determined in parallel in GR-cardiac mice (about 74 GR up-regulated genes and 70 GR down-regulated genes). Moreover, most of the MR-regulated genes did not change in the GR-cardiac mouse model, indicating that each steroid receptor controls a distinct pattern of gene expression in cardi...

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Abstract

The present invention relates to the use of Neutrophil Gelatinase-Associated Lipocalin (NGAL) and / or SERPINA3 as biomarkers of the Mineralocorticoid Receptor (MR) activation in a patient. More particularly, the present invention relates to a method for predicting the responsiveness of a patient to a treatment with a MR antagonist or an aldosterone synthase inhibitor, said method comprising determining in a biological sample obtained from said patient the expression level of the NGAL gene and / or of the SERPINA3 gene.

Description

FIELD OF THE INVENTION[0001]The present invention relates to biomarkers of the Mineralocorticoid Receptor (MR) activation in a patient.BACKGROUND OF THE INVENTION[0002]Mineralocorticoid receptor (MR) is a member of the classic steroid hormone receptors that include glucocorticoid receptor (GR), androgen receptor (AR), progesterone receptor (PR), and estrogen receptor (ER) (Funder, 1997). These receptors are hormone-activated transcriptional factors that regulate a wide variety of physiological processes ranging from organ development and differentiation to mood control and stress response (Beato et al., 1995). The physiological hormone for MR is aldosterone which is a steroid hormone secreted by the adrenal gland.[0003]MRs have been located on non-epithelial sites in blood vessels, brain, and heart (Bonvalet J P. et al. 1995; Lombes M, et al. 1992; Tanaka J. et al. 1997). Numerous studies over the past 10 years suggest that the non-epithelial actions of mineralocorticoids are respon...

Claims

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Application Information

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IPC IPC(8): A61K31/585G01N33/566A61P3/00A61P9/00A61P3/10A61P3/04C12Q1/68A61K31/5685
CPCC12Q1/6883C12Q2600/158G01N33/6893C12Q2600/106G01N2800/321G01N2800/325G01N2800/52G01N2800/32A61P3/00A61P3/04A61P43/00A61P9/00A61P9/10A61P3/10G01N33/6803G01N2800/04G01N2800/042G01N2800/044
Inventor JAISSER, FREDERICFARMAN, NICOLETTESAINTE-MARIE, YANNISLATOUCHE, CELINESTEENMAN, MARJA
Owner INST NAT DE LA SANTE & DE LA RECHERCHE MEDICALE (INSERM)
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